Racial and ethnic differences in epithelial ovarian cancer risk: an analysis from the Ovarian Cancer Association Consortium.

BACKGROUND: Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander (NHPI) women. METHODS: Participants included 1734 Asian (785 cases, 949 controls), 266 NHPI (99 cases, 167 controls), 1149 Hispanic (505 cases, 644 controls), and 24,189 White (9,981 cases, 14,208 controls) women from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for risk associations by race and ethnicity. RESULTS: Heterogeneity in EOC risk associations by race and ethnicity (p ≤ 0.02) was observed for oral contraceptive (OC) use, parity, tubal ligation and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in NHPI and Asian women. The inverse association for tubal ligation with risk was most pronounced for NHPI participants (OR=0.25, 95% CI 0.13-0.48), versus Asian and White participants, respectively (OR=0.68, 95% CI 0.51-0.90; OR=0.78, 95% CI 0.73-0.85). CONCLUSIONS: Differences in EOC risk factor associations were observed across racial and ethnic groups, which could in part be due to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies.

Exome sequencing identifies HELB as a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer.

Rare, germline loss-of-function variants in a handful of genes that encode DNA repair proteins have been shown to be associated with epithelial ovarian cancer with a stronger association for the high-grade serous hiostotype. The aim of this study was to collate exome sequencing data from multiple epithelial ovarian cancer case cohorts and controls in order to systematically evaluate the role of coding, loss-of-function variants across the genome in epithelial ovarian cancer risk. We assembled exome data for a total of 2,573 non-mucinous cases (1,876 high-grade serous and 697 non-high grade serous) and 13,925 controls. Harmonised variant calling and quality control filtering was applied across the different data sets. We carried out a gene-by-gene simple burden test for association of rare loss-of-function variants (minor allele frequency < 0.1%) with all non-mucinous ovarian cancer, high grade serous ovarian cancer and non-high grade serous ovarian cancer using logistic regression adjusted for the top four principal components to account for cryptic population structure and genetic ancestry. Seven of the top 10 associated genes were associations of the known ovarian cancer susceptibility genes BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH6 and PALB2 (false discovery probability < 0.1). A further four genes (HELB, OR2T35, NBN and MYO1A) had a false discovery rate of less than 0.1. Of these, HELB was most strongly associated with the non-high grade serous histotype (P = 1.3×10-6, FDR = 9.1×10-4). Further support for this association comes from the observation that loss of function variants in this gene are also associated with age at natural menopause and Mendelian randomisation analysis shows an association between genetically predicted age at natural menopause and endometrioid ovarian cancer, but not high-grade serous ovarian cancer.

Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease.

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10-8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

Risk Factors for Ovarian Cancer by BRCA Status: A Collaborative Case-Only Analysis.

BACKGROUND: Women with an inherited pathogenic variant in BRCA1 or BRCA2 have a greatly increased risk of developing ovarian cancer, but the importance of behavioral factors is less clear. We used a case-only design to compare the magnitude of associations with established reproductive, hormonal, and lifestyle risk factors between BRCA mutation carriers and noncarriers. METHODS: We pooled data from five studies from the Ovarian Cancer Association Consortium including 637 BRCA carriers and 4,289 noncarriers. Covariate-adjusted generalized linear mixed models were used to estimate interaction risk ratios (IRR) and 95% confidence intervals (CI), with BRCA (carrier vs. noncarrier) as the response variable. RESULTS: IRRs were above 1.0 for known protective factors including ever being pregnant (IRR = 1.29, 95% CI; 1.00-1.67) and ever using the oral contraceptive pill (1.30, 95% CI; 1.07-1.60), suggesting the protective effects of these factors may be reduced in carriers compared with noncarriers. Conversely, the IRRs for risk factors including endometriosis and menopausal hormone therapy were below 1.0, suggesting weaker positive associations among BRCA carriers. In contrast, associations with lifestyle factors including smoking, physical inactivity, body mass index, and aspirin use did not appear to differ by BRCA status. CONCLUSIONS: Our results suggest that associations with hormonal and reproductive factors are generally weaker for those with a pathogenic BRCA variant than those without, while associations with modifiable lifestyle factors are similar for carriers and noncarriers. IMPACT: Advice to maintain a healthy weight, be physically active, and refrain from smoking will therefore benefit BRCA carriers as well as noncarriers.

Leveraging GWAS: Path to Prevention?

Developing novel cancer prevention medication strategies is important for reducing mortality. Identification of common genetic variants associated with cancer risk suggests the potential to leverage these discoveries to define causal targets for cancer interception. Although each risk variant confers small increases in risk, researchers propose that blocking those that produce causal carcinogenic effects might have large impacts on cancer prevention. While a promising concept, we describe potential hurdles that may need to be scaled to reach this goal, including: (i) understanding the complexity of risk; (ii) achieving statistical power in studies with binary outcomes (cancer development: yes or no); (iii) characterization of cancer precursors; (iv) heterogeneity of cancer subtypes and the populations in which these diseases occur; (v) impact of static genetic markers across complex events of the life course; (vi) defining gene-gene and gene-environment interactions and (vii) demonstrating functional effects of markers in human populations. We assess short-term prospects for this research against the backdrop of these challenges and the potential to prevent cancer through other means. See related commentary by Peters and Tomlinson, p. 7.

Benign Breast Disease and Breast Cancer Risk in the Percutaneous Biopsy Era.

Importance: Benign breast disease (BBD) comprises approximately 75% of breast biopsy diagnoses. Surgical biopsy specimens diagnosed as nonproliferative (NP), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH) are associated with increasing breast cancer (BC) risk; however, knowledge is limited on risk associated with percutaneously diagnosed BBD. Objectives: To estimate BC risk associated with BBD in the percutaneous biopsy era irrespective of surgical biopsy. Design, Setting, and Participants: In this retrospective cohort study, BBD biopsy specimens collected from January 1, 2002, to December 31, 2013, from patients with BBD at Mayo Clinic in Rochester, Minnesota, were reviewed by 2 pathologists masked to outcomes. Women were followed up from 6 months after biopsy until censoring, BC diagnosis, or December 31, 2021. Exposure: Benign breast disease classification and multiplicity by pathology panel review. Main Outcomes: The main outcome was diagnosis of BC overall and stratified as ductal carcinoma in situ (DCIS) or invasive BC. Risk for presence vs absence of BBD lesions was assessed by Cox proportional hazards regression. Risk in patients with BBD compared with female breast cancer incidence rates from the Iowa Surveillance, Epidemiology, and End Results (SEER) program were estimated. Results: Among 4819 female participants, median age was 51 years (IQR, 43-62 years). Median follow-up was 10.9 years (IQR, 7.7-14.2 years) for control individuals without BC vs 6.6 years (IQR, 3.7-10.1 years) for patients with BC. Risk was higher in the cohort with BBD than in SEER data: BC overall (standard incidence ratio [SIR], 1.95; 95% CI, 1.76-2.17), invasive BC (SIR, 1.56; 95% CI, 1.37-1.78), and DCIS (SIR, 3.10; 95% CI, 2.54-3.77). The SIRs increased with increasing BBD severity (1.42 [95% CI, 1.19-1.71] for NP, 2.19 [95% CI, 1.88-2.54] for PDWA, and 3.91 [95% CI, 2.97-5.14] for AH), comparable to surgical cohorts with BBD. Risk also increased with increasing lesion multiplicity (SIR: 2.40 [95% CI, 2.06-2.79] for ≥3 foci of NP, 3.72 [95% CI, 2.31-5.99] for ≥3 foci of PDWA, and 5.29 [95% CI, 3.37-8.29] for ≥3 foci of AH). Ten-year BC cumulative incidence was 4.3% for NP, 6.6% for PDWA, and 14.6% for AH vs an expected population cumulative incidence of 2.9%. Conclusions and Relevance: In this contemporary cohort study of women diagnosed with BBD in the percutaneous biopsy era, overall risk of BC was increased vs the general population (DCIS and invasive cancer combined), similar to that in historical BBD cohorts. Development and validation of pathologic classifications including both BBD severity and multiplicity may enable improved BC risk stratification.

Age-Dependent Sex Differences in the Prevalence of Selective Serotonin Reuptake Inhibitor Treatment: A Retrospective Cohort Analysis.

Background: Antidepressants are among the most prescribed medications in the United States. The aim of this study was to explore the prevalence of antidepressant prescriptions and investigate sex differences and age-sex interactions in adults enrolled in the Right Drug, Right Dose, Right Time: Using Genomic Data to Individualize Treatment (RIGHT) study. Materials and Methods: We conducted a retrospective analysis of the RIGHT study. Using electronic prescriptions, we assessed 12-month prevalence of antidepressant treatment. Sex differences and age-sex interactions were evaluated using multivariable logistic regression and flexible recursive smoothing splines. Results: The sample consisted of 11,087 participants (60% women). Antidepressant prescription prevalence was 22.24% (27.96% women, 13.58% men). After adjusting for age and enrollment year, women had significantly greater odds of antidepressant prescription (odds ratio = 2.29; 95% confidence interval = 2.07, 2.54). Furthermore, selective serotonin reuptake inhibitors (SSRIs) had a significant age-sex interaction. While SSRI prescriptions in men showed a sustained decrease with age, there was no such decline for women until after reaching ∼50 years of age. There are important limitations to consider in this study. Electronic prescription data were cross-sectional; information on treatment duration or adherence was not collected; this cohort is not nationally representative; and enrollment occurred over a broad period, introducing confounding by changes in temporal prescribing practices. Conclusions: Underscored by the significant interaction between age and sex on odds of SSRI prescription, our results warrant age to be incorporated as a mediator when investigating sex differences in mental illness, especially mood disorders and their treatment.

Mendelian randomization in hepatology: A review of principles, opportunities, and challenges.

Mendelian randomization has become a popular tool to assess causal relationships using existing observational data. While randomized controlled trials are considered the gold standard for establishing causality between exposures and outcomes, it is not always feasible to conduct a trial. Mendelian randomization is a causal inference method that uses observational data to infer causal relationships by using genetic variation as a surrogate for the exposure of interest. Publications using the approach have increased dramatically in recent years, including in the field of hepatology. In this concise review, we describe the concepts, assumptions, and interpretation of Mendelian randomization as related to studies in hepatology. We focus on the strengths and weaknesses of the approach for a non-statistical audience, using an illustrative example to assess the causal relationship between body mass index and NAFLD.

Long-term effects of premenopausal bilateral oophorectomy with or without hysterectomy on physical aging and chronic medical conditions.

OBJECTIVE: We examined the long-term effects of premenopausal bilateral oophorectomy (PBO) with or without concurrent or preceding hysterectomy on physical and cognitive function and on odds of chronic conditions. METHODS: We enrolled 274 women with PBO with or without concurrent or preceding hysterectomy and 240 referents aged 55 years and older who were residents of Olmsted County, MN as of the PBO or index date. Chronic conditions were assessed via medical record abstraction. Cognitive diagnoses were based on neurocognitive testing. A physical function assessment included measures of strength and mobility. Multivariable regression models compared characteristics for women with PBO <46 years, PBO 46-49 years, and referent women with adjustments for age and other confounders. RESULTS: The clinical visits (median age, 67 years) were a median of 22 years after the PBO or index date. Of 274 women with PBO, 161 (59%) were <46 years at PBO and 113 (41%) were 46-49 years. Compared with referents, women with a history of PBO <46 years had increased odds of arthritis (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.06-2.55), asthma (OR, 1.74; 95% CI, 1.03-2.93), obstructive sleep apnea (OR, 2.00; 95% CI, 1.23-3.26), and bone fractures (OR, 2.86; 95% CI, 1.17-6.98), and walked a shorter mean distance on a 6-minute walk test ( b = -18.43; P = 0.034). Compared with referents, women with a history of PBO at age 46-49 years had increased odds of arthritis (OR, 1.92; 95% CI, 1.16-3.18) and obstructive sleep apnea (OR, 2.21; 95% CI, 1.33-3.66). There were no significant differences in cognitive status in women with PBO compared with referents. CONCLUSIONS: Women with a history of PBO with or without concurrent or preceding hysterectomy, especially at age <46 years, have more chronic conditions in late mid-life compared with referents.

Leadership Development in Early Career Scientists: Themes and Feedback from Executive Coaching and Mindful Leadership Training.

Background: Career development is essential for all academic stages, but particularly critical for the growth and retention of early career scientists. In addition to scientific technical training, professional skill development is crucial for the upward transition from postdoctoral trainee to early faculty member and beyond. Building leadership skills, specifically, is an important component of professional development, and the evaluation and reporting of professional development are important to improve and enhance the impact of programs. Methods: The purpose of this article is to share the program evaluation performed on leadership development activities, including executive coaching and mindful leadership training provided to a small group of early career scientists who participated in the National Institutes of Health (NIH)-funded Mayo Clinic Specialized Center of Research Excellence (SCORE) in Sex Differences Career Enhancement Core and Building Interdisciplinary Research Careers in Women's Health (BIRCWH) K12 programs during 2020-2022. Results: Eighty-seven percent of participants rated their satisfaction with the executive coaching program as "Very Satisfied" or "Satisfied," and 75% of participants were "Very Satisfied" or "Satisfied" with the mindful leadership training program. The findings of this program evaluation highlight the value of communication skills for navigating precarious situations, building self-efficacy and intentionality in making and holding boundaries for an individual's time and energy. Further, the individualized small group format of the activities allowed for deeper introspection and peer to peer connection. Conclusion: The identification of common themes within the Mayo Clinic program provides guidance to other academic environments on areas where they can support their early career scientists.

Quality control and analytic best practices for testing genetic models of sex differences in large populations.

Phenotypic sex-based differences exist for many complex traits. In other cases, phenotypes may be similar, but underlying biology may vary. Thus, sex-aware genetic analyses are becoming increasingly important for understanding the mechanisms driving these differences. To this end, we provide a guide outlining the current best practices for testing various models of sex-dependent genetic effects in complex traits and disease conditions, noting that this is an evolving field. Insights from sex-aware analyses will not only teach us about the biology of complex traits but also aid in achieving the goals of precision medicine and health equity for all.

Toward a deeper understanding of gene-by-sex interaction models.

In this issue of Cell Genomics, Zhu et al.1 propose amplification as the primary mode for gene-by-sex interactions in complex traits. Khramtsova et al. preview their modeling approach and discuss implications for the future work on the genomics of sex differences.

Impact of Artificial Intelligence System and Volumetric Density on Risk Prediction of Interval, Screen-Detected, and Advanced Breast Cancer.

PURPOSE: Artificial intelligence (AI) algorithms improve breast cancer detection on mammography, but their contribution to long-term risk prediction for advanced and interval cancers is unknown. METHODS: We identified 2,412 women with invasive breast cancer and 4,995 controls matched on age, race, and date of mammogram, from two US mammography cohorts, who had two-dimensional full-field digital mammograms performed 2-5.5 years before cancer diagnosis. We assessed Breast Imaging Reporting and Data System density, an AI malignancy score (1-10), and volumetric density measures. We used conditional logistic regression to estimate odds ratios (ORs), 95% CIs, adjusted for age and BMI, and C-statistics (AUC) to describe the association of AI score with invasive cancer and its contribution to models with breast density measures. Likelihood ratio tests (LRTs) and bootstrapping methods were used to compare model performance. RESULTS: On mammograms between 2-5.5 years prior to cancer, a one unit increase in AI score was associated with 20% greater odds of invasive breast cancer (OR, 1.20; 95% CI, 1.17 to 1.22; AUC, 0.63; 95% CI, 0.62 to 0.64) and was similarly predictive of interval (OR, 1.20; 95% CI, 1.13 to 1.27; AUC, 0.63) and advanced cancers (OR, 1.23; 95% CI, 1.16 to 1.31; AUC, 0.64) and in dense (OR, 1.18; 95% CI, 1.15 to 1.22; AUC, 0.66) breasts. AI score improved prediction of all cancer types in models with density measures (PLRT values < .001); discrimination improved for advanced cancer (ie, AUC for dense volume increased from 0.624 to 0.679, Δ AUC 0.065, P = .01) but did not reach statistical significance for interval cancer. CONCLUSION: AI imaging algorithms coupled with breast density independently contribute to long-term risk prediction of invasive breast cancers, in particular, advanced cancer.

Pharmacotherapy exposure as a marker of disease complexity in bipolar disorder: Associations with clinical & genetic risk factors.

Individuals with bipolar disorder (BD) require chronic pharmacotherapy, typically including medication switches or polypharmacy due to persisting symptoms or intolerable side effects. Here, we quantified pharmacotherapy exposure (PE) of Mayo Clinic BD Biobank participants using the number of cross-sectional (at enrollment) and lifetime BD-specific medications and medication classes, to understand the relationship between PE and markers of disease severity or treatment failure, psychiatric comorbidities, and polygenic risk scores (PRS) for six major psychiatric disorders. Being female (p < 0.05), older (p < 0.01), having history of suicide attempts (p < 0.0001), and comorbid attention-deficit/hyperactivity disorder (p < 0.05) or generalized anxiety disorder (p < 0.05) were uniformly associated with higher PE. Lifetime exposure to unique medication classes among participants with BD-I was significantly lower than for those with schizoaffective disorder (estimate = -2.1, p < 0.0001) while significantly higher than for those with BD-II (estimate = 0.5, p < 0.01). Further, higher PRS for schizophrenia (SCZ) and anxiety resulted in greater lifetime medication counts (p < 0.01), both driven by antipsychotic (p < 0.001) and anxiolytic use (p < 0.05). Our results provide initial evidence of the utility of PE as a measure of disease complexity or treatment resistance, and that PE may be predicted by higher genetic risk for SCZ and anxiety.

Polygenic prediction of bipolar disorder in a Latin American sample.

To date, bipolar disorder (BD) genetic studies and polygenic risk scores (PRSs) for BD are based primarily on populations of European descent (EUR) and lack representation from other ancestries including Latin American (LAT). Here, we describe a new LAT cohort from the Mayo Clinic Bipolar Biobank (MCBB), a multisite collaboration with recruitment sites in the United States (EUR; 1,443 cases and 777 controls) and Mexico and Chile (LAT; 211 cases and 161 controls) and use the sample to explore the performance of a BD-PRS in a LAT population. Using results from the largest genome-wide association study of BD in EUR individuals, PRSice2 and LDpred2 were used to compute BD-PRSs in the LAT and EUR samples from the MCBB. PRSs explained up to 1.4% (PRSice) and 4% (LDpred2) of the phenotypic variance on the liability scale in the LAT sample compared to 3.8% (PRSice2) and 3.4% (LDpred2) in the EUR samples. Future larger studies should further explore the differential performance of different PRS approaches across ancestries. International multisite studies, such as this one, have the potential to address diversity-related limitations of prior genomic studies and ultimately contribute to the reduction of health disparities.

Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma.

BACKGROUND: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features. METHODS: We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1. RESULTS: Methylation signature was associated with shorter time to recurrence, independent of clinical factors (N = 715 new set, hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.10-2.46; P = 0.015; N = 325 published set HR, 2.87; 95% CI, 2.17-3.81; P = 2.2 × 10-13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N = 599; HR, 2.22; 95% CI, 1.66-2.95; P = 4.1 × 10-8). Methylation signature was inversely related to CD8+ TIL levels (P = 2.4 × 10-7) and TAP1 expression (P = 0.0011) and was associated with gene expression molecular subtype (P = 5.9 × 10-4) in covariate-adjusted analysis. CONCLUSIONS: Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment. IMPACT: This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial.

Benign Breast Disease, NSAIDs, and Postmenopausal Breast Cancer Risk in the CPS-II Cohort.

ABSTRACT: Nonsteroidal anti-inflammatory agents (NSAID) are associated with modest inconsistent reductions in breast cancer risk in population-based cohorts, whereas two focused studies of patients with benign breast disease (BBD) have found lower risk with NSAID use. Given that BBD includes fibroinflammatory lesions linked to elevated breast cancer risk, we assessed whether NSAID use was associated with lower breast cancer risk among patients with BBD.Participants were postmenopausal women in the Cancer Prevention Study-II (CPS-II), a prospective study of cancer incidence and mortality, who completed follow-up surveys in 1997 with follow-up through June 30, 2015. History of BBD, NSAID use, and covariate data were updated biennially. This analysis included 23,615 patients with BBD and 36,751 patients with non-BBD, including 3,896 incident breast cancers over an average of 12.72 years of follow-up among participants. NSAID use, overall and by formulation, recency, duration, and pills per month was analyzed versus breast cancer risk overall and by BBD status using multivariable-adjusted Cox models; BBD status and NSAID use were modeled as time-dependent exposures.Patients with BBD who reported using NSAIDs experienced lower breast cancer risk (HR, 0.87; 95% CI, 0.78-0.97), with similar effects for estrogen receptor (ER)-positive breast cancers [HR, 0.85; 95% confidence interval (CI), 0.74-0.97] and ER-negative breast cancers (HR, 0.87; 95% CI, 0.59-1.29); among women without BBD, NSAID use was unrelated to risk (HR, 1.02; 95% CI, 0.92-1.13; Pinteraction = 0.04). Associations stratified by age, obesity, menopausal hormone use, and cardiovascular disease were similar.Among patients with BBD, NSAID use appears linked to lower breast cancer risk. Further studies to assess the value of NSAID use among patients with BBD are warranted. PREVENTION RELEVANCE: We examined whether NSAID use, a modifiable exposure, is associated with breast cancer risk in postmenopausal women from the Cancer Prevention Study-II with self-reported benign breast disease, an often inflammatory condition associated with higher rates of breast cancer.

Associations of sex-related steroid hormones and proteins with alcohol dependence: A United Kingdom Biobank study.

BACKGROUND: Sex-related steroid hormones and proteins may contribute to the sex differences in the characteristics and health consequences of alcohol use disorder. This study aimed to examine the associations between alcohol dependence (AD) and sex-related hormones/proteins using a population-based dataset. METHODS: We retrieved serum total testosterone (TT) and estradiol (TE2), sex hormone binding globulin (SHBG), and albumin levels along with clinical data from the UK Biobank. Hormone/protein levels were compared between AD (lifetime AD and/or related diagnoses; 2218 males; 682 females) and control (no aforementioned diagnoses and AUDIT<8; 198,058 males; 250,830 females) groups with sex-dependent linear regression models adjusting for age and body mass index. Moderation and mediation analyses were performed to test whether SHBG was a moderator and/or mediator between hormones and AD or current drinking. RESULTS: AD males had higher TT, TE2, and SHBG levels but lower bioavailable testosterone, bioavailable estradiol, and albumin levels than controls (padjusted<0.001). After adjusting for menopause, AD females had higher TT and lower albumin levels than controls (padjusted<0.001). These differences remained after accounting for current drinking frequency (p < 0.001). SHBG moderated TT's effect on AD in males (pinteraction<0.001). SHBG was a positive mediator between TT and AD in both sexes and between TE2 and AD in males (p < 0.001), but a negative mediator between TT and current drinking in controls (both sexes) and AD males (p < 0.001). CONCLUSIONS: Testosterone and estradiol levels are altered in males and females with AD distinctly regardless of current drinking frequency. SHBG may play a critical role in these associations.

The Interaction Between Brain-Derived Neurotrophic Factor Levels and Alcohol Consumption, Sleep Disturbance and Sex-Hormones in Alcohol Use Disorders.

AIMS: Brain-derived neurotrophic factor (BDNF) levels may be associated with alcohol use disorders (AUD) and alcohol consumption, correlate with sleep disturbance and be influenced by sex differences and sex hormones. These associations have not been examined in a single sample accounting for all these factors. METHODS: Data from 190 participants (29.4% female) with AUD were utilized. Sleep quality, craving intensity, depression, anxiety and alcohol consumption were assessed using the Pittsburgh Sleep Quality Index (PSQI), Penn Alcohol Craving Scale (PACS), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7) and Timeline Follow Back for 90 days(TLFB 90). Inventory of Drug Taking Situations (IDTS) assessed the tendency to drink in positive/negative emotional states. Serum BDNF (sBDNF) and plasma sex hormones (estrogen, progesterone, testosterone, FSH and SHBG) were measured. Pearson correlation analyses were used to examine the association between sBDNF and these measures in the entire sample and in men and women separately. Higher order interaction effects between these factors were evaluated for their association with sBDNF using a backward selection model. RESULTS: No significant correlations between sBDNF levels and sex hormones, PSQI, PHQ-9, PACS, IDTS scores and alcohol consumption were found (all P-values > 0.05). sBDNF levels were negatively correlated with GAD-7 scores in men (r = -0.1841; P = 0.03). When considering all quadratic and two-way interactions among PSQI, PHQ-9, GAD-7, mean and max drinks/day, number of drinking days, heavy drinking days, and sex no higher order moderating effects of sBDNF levels were found. CONCLUSION: Our study revealed no significant associations between sBDNF and alcohol measures, sleep, depression and sex hormones suggesting limited utility as a biomarker.

The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer.

Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes and differential immune responses appear to contribute to long-term survival in HGSC.